Continuous positive airway pressure alters cranial blood flow and cerebrospinal fluid dynamics at the craniovertebral junction Theresia I. Yiallourou, Marianne Schmid Daners, Vartan Kurtcuoglu, Jose Haba-Rubio, Raphael Heinzer, Eleonora Fornani, Francesco Santini, Daniel B. Sheffer, Nikolaos Stergiopulos, Bryn A. Martin PII: DOI: Reference:
S2214-7519(15)30005-0 doi: 10.1016/j.inat.2015.06.004 INAT 77
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Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
Received date: Revised date: Accepted date:
23 July 2014 20 May 2015 13 June 2015
Please cite this article as: , Continuous positive airway pressure alters cranial blood flow and cerebrospinal fluid dynamics at the craniovertebral junction, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management (2015), doi: 10.1016/j.inat.2015.06.004
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ACCEPTED MANUSCRIPT TITLE PAGE TITLE OF THE ARTICLE: Continuous positive airway pressure alters cranial blood flow and cerebrospinal fluid dynamics at the craniovertebral junction
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AUTHORS Theresia I. Yiallourou1, Marianne Schmid Daners2, Vartan Kurtcuoglu3, Jose Haba-Rubio4, Raphael Heinzer4, Eleonora Fornani5, Francesco Santini6, Daniel B. Sheffer7, Nikolaos Stergiopulos1, Bryn A. Martin8
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AUTHOR AFFILIATIONS: 1 Laboratory of Hemodynamics and Cardiovascular Technology, École Polytechnique Fédérale de Lausanne, Switzerland 2 Institute for Dynamic Systems and Control and Product Development Group Zurich, Department of Mechanical and Process Engineering, ETH Zurich, Switzerland 3 The Interface Group, Institute of Physiology, Zurich Center for Integrative Human Physiology and Neuroscience Center Zurich, University of Zurich, Switzerland 4 Centre Hospitalier Universitaire Vaudois (CHUV), Centre for Investigation and Research on Sleep (CIRS), Lausanne, Switzerland 5 Center for Biomedical Imaging (CIBM), CHUV, Lausanne, Switzerland 6 Radiological Physics, University of Basel Hospital, Basel, Switzerland 7 Department of Biomedical Engineering, University of Akron, OH, U.S.A 8 Conquer Chiari Research Center, Department of Mechanical Engineering, The University of Akron, OH, U.S.A Theresia I. Yiallourou and Marianne Schmid Daners contributed equally to this work
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CORRESPONDING AUTHOR Bryn A. Martin Conquer Chiari Research Center University of Akron, Akron, OH 44325-3903
[email protected] Phone: +1 330 475 9747 Fax: +1 330 972 6027 EMAIL ADDRESSES
[email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected]
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ACCEPTED MANUSCRIPT ABSTRACT Purpose: To investigate the impact of continuous positive airway pressure (CPAP) applied by a full-face fitted mask at 15 cmH2O on total cerebral blood flow (tCBF), jugular venous flow (tJVF) and cerebrospinal fluid (CSF) flow.
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Materials and Methods: Axial 2D phase-contrast MRI measurements were acquired at the C2-C3 vertebral level
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for 23 healthy male awake subjects at baseline (without) and with CPAP applied. CSF flow was quantified within the spinal subarachnoid space and tCBF was quantified based on the summation of blood flow within the left and right
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internal carotid and vertebral arteries. tJVF was quantified based on the summation of blood flow within the left and
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right jugular veins. Heart rate, transcutaneous carbon dioxide (PtcCO2) and oxygen saturation were continuously monitored during the MR protocol.
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Results: CPAP decreased the pulse amplitude (PtPPA) of tJVF by 21% (p=0.004). CSF stroke volume (SV) and PtPPA also decreased by 20% (p=0.003) and 15% (p=0.005), respectively. Change in tCBF SV and PtPPA was not
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significant. However, the timing of maximum systolic tCBF occurred significantly earlier under CPAP. CSF flow and tJVF
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waveforms showed significant spatial and temporal differences in waveform feature points, and spectral analysis revealed a decrease in the first harmonic of tJVF under CPAP (p=0.001). Under CPAP, a 5% decrease in PtcCO2 (p=0.003)
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and 9% increase in HR (p=0.006) were measured. However, these HR and PtcCO2 changes were not correlated with any
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changes in arterial, venous or CSF flow dynamics. Conclusion: Application of CPAP via a full-fitted mask at 15 cm H2O was found to have a significant effect on intracranial venous outflow and spinal CSF flow at the C2 vertebral level in healthy adult-age awake volunteers . CPAP can be used to non-invasively provoke changes in intracranial and CSF flow dynamics. KEYWORDS Cerebral blood flow, cerebrospinal fluid dynamics, spinal subarachnoid space, cerebral autoregulation, cervical spine, continuous positive airway pressure, sleep apnea, intrathoracic pressure, craniospinal compliance, PtcCO2 , 2D phasecontrast MRI
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ACCEPTED MANUSCRIPT INTRODUCTION The coupling of cerebrospinal fluid (CSF) pressure fluctuations and the cardiovascular system have long interested researchers [1-3]. A full understanding of this coupling is thought to be important to understand the pathophysiology of cerebrovascular disorders such as stroke, interstitial fluid transport within the brain [4, 5], and
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craniospinal disorders such as type I Chiari malformation, syringomyelia and hydrocephalus [6-9]. A number of studies have sought to understand the CSF dynamics in the spinal subarachnoid space (SSS) and its importance for the overall
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intracranial balance between the arterial, venous, and CSF flow pulsations[10-12]. Researchers have postulated that under normal conditions the healthy SSS may act as a “notch filter” that dampens incoming cerebral blood flow (CBF)
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pulsations to supply smooth blood flow to the neural tissue[13, 14]. In addition, Martins et al.[15] showed that the spinal dural sac is a dynamic structure, readily changing its capacity in response to intra-abdominal pressure
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fluctuations.
Non-invasive 2D phase-contrast magnetic resonance imaging (2D PC MRI) enables measurement of the CSF and
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CBF system fluid flow[16, 17] and has also been used to estimate venous flow in the jugular and intracerebral veins as
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well as the major sinuses[12]. According to the Monro–Kellie doctrine[12], the arterial, venous, CSF and brain tissue compartments co-exist in a state of dynamic equilibrium throughout the cardiac cycle[18-20]. A change in the volume
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in one component requires a change in the volume in either one or both of the other two compartments. Schmid
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Daners et al.[21] showed using 2D PC MRI that the coupling of cerebral arterial inflow and CSF dynamics is age and sex dependent. Other studies have focused on the cerebral venous system [20, 22]. El Sankari et al.[22] simultaneously compared the venous flow, arterial and CSF flows of patients with multiple scleroses to age and sex matched healthy adults. Results documented complex and heterogeneous venous drainage pathways and a decrease in CSF flow oscillations. The interaction between intrathoracic pressure and intracranial pressure (ICP) due to posture[23], abdominal pressure changes[24] and coughing[25] have been reported in the literature. These pressure changes are transmitted from the abdomen into the CSF system through the dural venous sinuses and epidural venous plexus[26]. Published data have shown physiologic variations in the dural venous sinus drainage that can occur either under specific respiratory mechanisms such as Valsava maneuver[27] or with posture changes[28]. Thus, it is possible to manipulate the intrathoracic pressure by a number of non-invasive maneuvers that in turn modify the intracranial system as a 3
ACCEPTED MANUSCRIPT whole. One method to non-invasively alter intrathoracic pressure is with the use of continuous positive airway pressure (CPAP), the most widely accepted treatment for sleep apnea. CPAP acts as a pneumatic “splint” by producing a positive pressure, thereby preventing upper airway collapse during sleep.
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While CPAP use has become routine, the full physiological effect of its use on CBF, venous flow and CSF
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dynamics is not fully understood[29, 30]. Considering that a rise of the intrathoracic pressure increases the jugular venous pressure, CPAP could have an effect on CBF by reducing the cerebral perfusion pressure[31]. Concomitantly,
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changes in the blood flow volume due to the increased intrathoracic pressure hinders cerebral venous drainage via the
reduce CSF peak velocity in the aqueduct of Sylvius[34].
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jugular veins[32]. In human volunteers CPAP breathing has been shown to increase lumbar CSF pressure[33] and
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In the present study, we hypothesized that acute pressure changes in the chest caused by the application of CPAP would alter intracranial and spinal CSF flow dynamics in the following manner: 1) venous flow dynamics would be
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noticeably altered and 2) the stroke volume (SV) and pulsation of the spinal CSF would decrease. We tested our hypothesis by applying CPAP at 15 cm H2O in 23 healthy male volunteers and measured physiological alterations using a
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2D PC MRI protocol to quantify blood flow in the left and right internal carotid arteries (ICA), left and right vertebral
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arteries (VA), left and right jugular veins (JV) and CSF flow at the C2-C3 level of the cervical spinal canal with CPAP applied. Baseline measurements without CPAP applied followed the initial recording with the CPAP using identical
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imaging protocols. Using these measurements the influence of CPAP on total cerebral blood flow (tCBF), total jugular venous (tJVF) and spinal CSF flow was assessed in terms of flow based metrics and spectral content of the flow waveforms.
MATERIALS AND METHODS Ethics statement Healthy, young, non-smoking male volunteers, with no history of pulmonary, cardiac, neurological, cerebral disease, spinal trauma or diagnosed sleep apnea, were invited to participate in the study by advertisement at the local university hospital of Lausanne, Centre Hospitalier Universitaire Vaudois (CHUV) and École Polytechnique Fédérale de Lausanne in Switzerland. The study was carried out in accordance with the Declaration of Helsinki (1989) and was 4
ACCEPTED MANUSCRIPT approved by the Swiss Human Research Ethics Committee of Vaud. The MR data acquisition was performed at the Centre d’Imagerie BioMédicale (CIBM) – Department of Radiology, CHUV in Lausanne. Before the MR exams, written
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informed consent was obtained for all volunteers. MR data were anonymized prior to data post-processing.
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In vivo 2D PC MR measurements
23 healthy male volunteers, aged 24±2.1 years with a mean body mass index (BMI) of 22.9±2.51 kg/m2 were
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scanned on a 3T MRI scanner (Siemens Magnetom Trio Tim, Siemens, Erlangen, Germany) with a standard 4-channel phased array carotid coil (Magnet Mach NET 4CHN, Siemens A Tim Coil), placed adjacent to the left and right ICA and a
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neck coil (Neck matrix, 4CHN, Siemens) with CPAP (S8 AutoSet SpiritTM II, ResMed Inc, Poway, CA) applied at 15 cmH2O
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through a fitted full-face mask MIRAGE QUATTRO® (ResMed®, ResMed Inc, Poway, CA) in a specific order following a structured protocol. The measurements were performed during the afternoon at atmospheric pressure in the MR
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scanner room with controlled temperature at least two hours after the last meal and caffeinated drink. A medical doctor was present throughout testing. Subjects were awake during the entire MRI protocol in the supine position with
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their necks in a neutral orientation.
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Both anatomy and 2D PC MR images were acquired. A set of T2-weighted turbo spin-echo sagittal images defined the anatomy in the upper cervical spine. Fluid flow acquisition planes, oriented perpendicular to the nominal
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flow direction, were selected based on a mid-sagittal scan at the C2-C3 subarachnoid space (Figure 1A). Both left and right ICAs, left and right VAs and left and right JVs were imaged by 2D PCMRI simultaneously within the same slice oriented orthogonal to the spinal cord axis at the C2-C3 cervical level (Figure 1B). Imaging parameters for the arterial and jugular flow measurements were as follows: 0.7 mm isotropic in-plane resolution, 5 mm slice thickness, 124X114 acquisition matrix, 20° flip angle, 814 Hz/Px bandwidth, 190x112 field of view (FoV), 59.4% FoV phase, 256 base resolution, 100% phase resolution, 80 cm/s thru-plane velocity encoding (VENC) and TR=20 ms and TE=6.5 ms, that resulted in a temporal resolution of 20 ms. The minimum TR available was used to optimize temporal resolution, and the minimum TE available was used to optimize signal-to-noise ratio and to reduce intravoxel phase dispersion. All scans were prospectively triggered with electrocardiographic (ECG) gating. The number of heart phases acquired was adapted to the cardiac frequency and fixed to 35 phases for all the subjects. 5
ACCEPTED MANUSCRIPT CSF flow measurements were performed at the same location as the vascular flow measurements (Figure 1C) with the imaging parameters identical to those of the vascular flow measurements, except with a VENC of 10 cm/s and 15° flip angle. Overall scan time was 8-10 minutes with CPAP and 8-10 minutes without CPAP applied, depending on the
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heart rate. The entire examination was approximately 45 minutes.
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Physiologic monitoring
Transcutaneous partial pressure of carbon dioxide (PtcCO2), oxygen saturation (SaO2) and heart rate (HR) were
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monitored throughout the exam with a ‘Tosca 500’ system (Radiometer Basel AG, Basel, Switzerland) using a sensor applied at the top surface of the foot. MRI measurements under CPAP were obtained first after the PtcCO2 level return
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to baseline (±2 mmHg) or at least 15 minutes of CPAP use. Following the MRI measurements with CPAP, the mask was
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removed and the same protocol repeated without CPAP to obtain the ‘baseline’ measurements. Following MR examination, all subjects were asked to rate their anxiety level under CPAP from a scale of 0-3 where 0 refers to ‘not at
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all anxious’, 1 refers to ‘slightly anxious’, 2 refers to ‘moderately anxious’ and 3 refers to ‘highly anxious’. Data processing and analysis
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All 2D PC MR images were post-processed with Segment (Standalone version, Medviso AB, Lund, Sweden) by
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one operator blinded to subject status. For each scan, flow was determined with an adaptive region of interest (ROI) selection using manual segmentation based on the instantaneous lumen area. Images were visually inspected for
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adequate signal to noise at the ROI. Datasets presenting major artifacts or too low signal levels were excluded from the subsequent analyses. Aliasing correction and eddy current compensation were performed automatically by the “unwrap” and “eddy current” function of the Phantom experiment method (GE method)[35] procedures in Segment. The ICAs, VAs and JVs were segmented frame by frame in order to account for the temporal change in their crosssection due to the blood pulsation. The cervical SSS was segmented in single-image frames since its cross-sectional area did not vary with time. The ROI of SSS was best outlined in early systole, when the contrast between CSF and spinal cord was at its maximum. Data visualization and post-processing were performed using image processing software within MATLAB R2010b (The Mathworks Inc., Natick, MA, USA). Flow waveforms were obtained from the recorded velocity for each voxel from the PC MR images and then integrated over the area of each ROI. The process involved integration of the 6
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velocity over the manually segmented cross-sectional area for an entire cardiac cycle: Q t
A V voxel
voxel
(t ) ,
where Avoxel is the area of the one MRI voxel, Vvoxel is the velocity of the corresponding voxel, and Q(t) is the voxel summation of the flow for each voxel of interest[17].
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The tCBF into the cranial space was calculated by summing the blood flow rates of the left and right ICAs and
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left and right VAs: tCBF Q(t ) ICAs Q(t )VAs , where Q(t ) ICAs and Q(t )VAs are calculated as the sum of the left and
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right vessel measurements (i.e, QICAs Q(t ) ICAleft Q(t ) ICAright and QVAs Q(t )VAleft Q(t )VAright ). Estimation of the tJVF was obtained by the summation of the flow rates through the left and right JVs: tJVF Q(t ) JVleft Q(t ) JVright . CSF
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flow waveform was offset so the net CSF flow per cycle was zero since the net flow in the SSS is known to be nearly
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zero[36].
The stroke volume (SV) (mL/cardiac cycle) was also determined for both the vascular and the spinal CSF
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compartments using the trapezoidal rule by computing volume changes for each time increment, which correspond to the area under the waveform curve of the flow difference into and out of the ROI.
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For the frequency and flow rate analysis, the data were temporally and spatially normalized according to
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Schmid Daners et al.[21]. The length of the cardiac cycle of the subjects with CPAP and during the baseline measurements was 0.94±0.17 s and 1.0±0.16 s, respectively. Therefore, the data were temporally normalized to 1 s and
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resampled with a time interval of 10 ms. The normalized cardiac cycle allows for comparison of frequency components (expressed in Hertz (Hz)) obtained via discrete Fourier transformation. The frequencies were considered up to the noise level of each compartment, which was evaluated with the standard deviation of the respective compartment signals over all volunteers. The frequency components below one-fifth standard deviation were considered as noise [21]. The zero frequency was not taken into account, because it does not correspond to the net flow due to the spatial normalization. The spinal CSF flow and the tJVF were spatially normalized by the average flow rate over the entire measurement length and the tCBF over the systole only. In general, the spatial normalization aimed at accentuating the flow characteristics. Statistical analysis
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ACCEPTED MANUSCRIPT Statistical analysis was conducted with Minitab 16 (State College, PA) and IBM SPSS Statistics 19 (SPSS Inc., Chicago, IL, US). A Mann-Whitney U test was performed when the variances between groups were not equal. Multivariate analysis of covariance (MANCOVA) was performed to investigate the combined effects of the independent
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group of variables (height, weight, BMI and age) on each of the calculated dependent variables. Non-normally
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distributed data were logarithmically transformed before analysis. Frequencies of normalized flow rates that were recorded with CPAP and during the baseline measurements were evaluated using repeated measures analysis of
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variance (ANOVA) with Greenhouse-Geisser correction to compensate for non-sphericity. The ANOVA was performed within both groups and between the data of the recordings with CPAP and baseline measurements. Individual
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frequency components were compared with a Mann-Whitney U test. Correlations were calculated with Spearman’s
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rho. Differences were considered significant at p-value < 0.05. RESULTS
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All results are presented as mean±standard deviation (SD) for the number of volunteers (n) whose measurements were taken into account (see Tables 1 and 2). Results were analyzed in terms of average flow, systolic
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and diastolic peak flow, peak-to-peak pulse amplitude (PtPPA), area and SV of both the vascular and CSF components.
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Characteristics of the waveforms of the tCBF, tJVF, and spinal CSF flow are described with respect to their feature points and frequency content.
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Physiological metrics
Under CPAP, a 5% decrease in PtcCO2 (p=0.003) and 9% increase in HR (p=0.006) were measured (Table 1). The changes in both HR and PtcCO2 were not correlated with any of the changes observed in the arterial, venous and CSF flow dynamics. In terms of the anxiety level, the results showed that 70% of the subjects tolerated the CPAP well, reporting “slight anxiety” with a mean value of 0.35±0.49 in the anxiety index. Anxiety was not correlated with any of the independent variables (height, weight, age, BMI). MANCOVA analysis showed that the independent group of variables (weight, height, age and BMI) had no significant effect on the PtPPA and the SV of the tCBF, the tJVF and the CSF flow. A significant effect was observed on HR change by the independent group (p = 0.03). MR-based area and flow metrics
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ACCEPTED MANUSCRIPT The area of tCBF that corresponds to the sum of areas of left and right ICA and VA decreased significantly under CPAP (3±1mm2, p=0.015). All other changes in arterial flow-based metrics under CPAP were insignificant (Table 2 and Figure 2A). Diastolic peak tJVF increased under CPAP by 40% (89±67mL/min,
